The rationale for PRAM-2 is to evaluate the virologic and therapeutic potential of novel combinations of antiretrovirals and to better define the pharmacokinetics and drug-drug interactions of therapies included in these regimens. In doing so, the number of therapeutic options available for antiretroviral experienced, HIV-infected, clinically stable children will be dramatically increased. A number of recent studies indicate that suppression of HIV replication is important in delaying clinical progression. High levels of plasma HIV RNA are strongly predictive of rapid clinical progression and large sustained decreases in plasma HIV-1 RNA as a consequence of antiviral therapy are strongly associated with a delay in clinical progression. For example in ACTG 152, patients randomized to ZDV had significantly more clinical endpoints and a smaller decrease in median plasma HIV RNA (0.32 log) at 24 weeks than patients randomized to AZT+ddI with a 0.9 log decrease. However, these decreases in plasma HIV RNA were relatively small considering the median plasma HIV RNA values in ACTG 152 were between 100,000 snd 1,000,000 copies/ml when stratified by age. Combination therapy with two nucleoside analogues and a protease inhibitor in adults has resulted in decreases of plasma HIV RNA to undetectable levels in 50-80% of patients at one year of follow-up. In ACTG 338, at the 12 week interim analysis, the proportion of children reaching an undetectable viral load on the ZDV plus 3TC arm was less than on the other two protease inhibitors containing treatment arms (p<0.001 for both comparisons). The median drop in RNA from baseline to week 12 was 0.33 logs for the ZDV plus 3TC group, and in the other two treatment groups was at the limit of detection (>1.6 logs in both groups). Therefore, the drug regimens proposed in this study were designed to result in a much larger sustained drop in plasma HIV-1 RNA and greater clinical benefits.